2,5-dimethylpyrazine p-toluenesulfonate



United States Patent Q US. Cl. 260250 1 Claim ABSTRACT OF THE DISCLOSURE Therapeutic composition and method for treating hyperlipidemia in mammals involving a 2,5 disubstituted pyrazine of the formula:

RI IT wherein R is alkyl and R is selected from the group consisting of alkyl, carboxyl, alkoxycarbonyl, carbamoyl and monoand dialkyl substituted carbamoyl, said alkyl groups containing 1 through 4 carbon atoms, and physiologically acceptable salts thereof.

This application is a continuation-in-part of application Ser. No. 389,791, filed Aug. 14, 1964, now abandoned.

The novel compounds and primary active ingredients utilized in the novel compositions and method of this invention are represented by the formula wherein R is alkyl and R is alkyl, carboxyl, alkoxycarbonyl, carbamoyl and monoand dialkyl-substituted carbamoyl, the alkyl groups containing 1 through 4 carbon atoms, and physiologically acceptable salts of the foregoing compounds. By salts is meant acid addition salts, such as the hydrochloride, cyclohexylsulfamate, sulfate, acetate, nitrate, phosphate, citrate, maleate, tartrate, succinate, pamoate, p-toluenesulfonate, benzenesulfonate and the like of the foregoing pyrazines; alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as aluminum, calcium and magnesium), amine salts (such as N,N-dibenzylethylenediamine, procaine and diethanolamine), and ammonium salts of the carboxypyrazines; and metal salt complexes of the formula wherein R and R are as above defined, nis an integer less than 3, and MS is a physiologically acceptable metal salt, such as the chlorides, bromides, phosphates, sulfates, nitrates, acetates and carbonates of Zinc, iron, aluminum, magnesium and calcium and the like.

The compounds of this invention are prepared by methods well known in the art, e.g., by the methods and obvious adaptations thereof described at J. Prakt. chim. (2) 47:455, 480 (1893) Chem. Abs. 42: P5055i (1948).

These compounds have been unexpectedly found to exhibit several times the oral hypoglycemic activity of tolbutamide in standard test animals. This pronounced activity is accompanied by a low order of toxicity, making pharmaceutical compositions containing such compounds useful in reducing the blood sugar content of mammals, and in particular for administration by the preferred oral route. These compounds as formulated herein are also useful in treating ketosis, as anti-inflammatory agents in the management of inflammatory conditions for which steroids are normally employed, and as diuretics.

It has also been discovered that representative compounds of the group here disclosed are effective in reducing the free fatty acids, cholesterol and triglycerides content of blood in mammals. These activities, demonstrated at acceptable therapeutic ratios, make the compounds herein useful as compositions in treating such conditions as atherosclerosis, arteriosclerosis, blood-clotting defects due to lipermia, and other clinical entities in which the underlying etiology is associated with lipid imbalance or hyperlipidemia.

In utilizing the compositions and practicing the method of this invention, the exact schedule of adminstration in animals is determined individually according to the subjects age, Weight, response to the medication and nature and severity of the condition being treated.

In addition to 2,5-disubstituted pyrazines as the sole active ingredient, other complementary ingredients can be included in the composition to secure advantageous combinations of properties especially adapted to individual situations in the treatment of the foregoing conditions. Thus, other hypoglycemic agents such as tolbutamide, N- (hexahydro 1 azepinyl carbamoyl)-p-toluenesulfonamide, chloropropamide, phenformin hydrochloride, 5- methylpyrazole-3-carboxylic acid, mesoxalic acid, insulin, nicotinic acid, and the like can be included in the present formulations in amounts not exceeding and preferably less than those normally employed in single unit doses where such added ingredients are employed alone. Utilizable potassium salts, such as potassium chloride, can be included to offset possible potassium losses during therapy.

Such combinations include also conventional therapeutic amounts or less of other hypocholesteremic agents such as the D-isomer of 3,5,3-triiodothyronine, triiodothyropropionic acid, and thyroxine-like compounds such as sodium L-thyroxine and sodium D-thyroxine; glucocorticoids such as hydrocortisone, prednisolone and 6a-methylprednisolone; anticoagulants such as heparin, 2-diphenylacetyl-1,3-indandione, polyethylene sulfonate and dimmarol or its derivatives; unsaturated fatty acids such as linoleic acid, linolenic acid and arachidonic acid or edible oils containing these unsaturated fatty acids such as purified linseed oil, soybean oil, safflower oil, corn oil, sardine oil, menhaden oil, and the like; vitamins such as nicotinic acid, vitamin B ascorbic acid and pyridoxine hydrochloride, estrogens such as estradiol; androgens such as testosterone and 7-methylandrostanes such as or 7B- methyl-5a-androstane-3fl,17,8-diol; combinations of estrogens and androgens such as estradiol and testosterone; antibiotics such as neomycin; analgesics such as aspirin; compounds associated with cholesterol synthesis or metabolism such as a-phenylbutyric acid, ethyl chlorophenoxyisobutyrate and a-p-biphenylylbutyric acid; lipotropic agents such as choline and inositol; amino acids such as taurine and glycine; sterols such as sitosterol and other plant sterols; diuretics such as ethoxzolamide and hydrochlorothiazide; anorexigenic agents such as amphetamine; cardiovascular agents (including vasodilators and hypotensive agents), such as chlorisondamine chloride, hexamethonium chloride, and pentaerythritol tetranitrate.

In adapting the active ingredients for use in mammals the novel compositions are suitably presented for administration in unit dosage form as tablets, pills, capsules, powders, wafers, cachets, granules, oral or parenteral fluid preparations, including elixirs, aqueous and oil dispersions and the like.

For preparing solid compositions such as tablets, the active ingredient is mixed with a conventional non-sugar tableting component such as cornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, calcium stearate, gums, and functionally similar materials constituting pharmaceutical diluents, granulating agents or carriers. The tablets or pills can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or of predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalate and the like. A particularly advantageous sustained release coating comprises a styrene maleic acid copolymer.

The liquid form in which the novel compositions of this invention can be incorporated include oil disperions or emulsions, aqueous sugar-free solutions or suspensions, emulsions or suspensions with edible oils such as soybean oil, purified linseed oil, cottonseed oil, sesame oil, corn oil, safliower oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include the synthetic and natural gums such as tragacanth, acacia, alginate, dextran, methylcellulose, polyvinylpyrrolidone, gelatin and the like.

In preparing pharmaceutical compositions of 2,5-dimethyl-pyrazine, the fact that this compound is a volatile liquid must be considered. (Salts, such as the hydrochloride, are solid but may be discolored on contact with metals.) Appropriate oral liquid dosage forms include conventional sugar-free syrups, elixirs and solutions for use as drops or by the teaspoonful. Suitable non-aqueous vehicles for oral use include the edible oils (e.g., purified linseed oil, corn oil, cottonseed oil, soybean oil and other vegetable oils), mineral oil, glycerol, propylene glycol, polyethylene glycol 200-600, sorbitol, ethanol, or mixtures of these (e.g., equal parts of soybean oil and propylene glycol). Aqueous vehicles are also suitable. Liquid preparations for intramuscular or subcutaneous injection can be prepared as ethanolic-aqueous, propylene glycol-aqueous or oil solutions (e.g., vegetable oils such as peanut oil) and in repository-type vehicles such as aluminum monostearate-peanut oil gel. In general, liquid formulations range in concentration from about 05-50% 2,5-dimethylpyrazine.

The solid dosage forms of 2,5-dimethylpyrazine require the intermediate preparation of the liquid active ingredient as discrete solid particles which can be employed to build the ultimate dosage form by conventional methods. Alternatively, the 2,5-dimethylpyrazine can be dissolved or dispersed in an edible oil such as a vegetable or mineral oil (in ratios of, for example, about 1:1 to 1:200) and soft elastic capsules containing the oil dispersion or solution prepared for oral use. Triturates of 2,5-dimethylpyrazine can be made using various absorbing powders such as kaolin, magnesium carbonate, bentonite, magnesium oxide, starch, calcium carbonate, tribasic calcium phosphate, magnesium trisilicate and the like. Emulsifying the liquid 2,5-dimethylpyrazine, preferably dissolved in a suitable vegetable oil or mineral oil, to provide small particle sizes and then coating the said particles with a coacervate of one or more hydrophilic colloids, pharmaceutically acceptable copolymers, or mixtures thereof yields, on drying, free-flowing granulations which can be handled essentially as solid particles and formulated as powders, granules, tablets, hard-filled capsules and the like. Solid metal salt complexes of the liquid 2,5-dirnethylpyrazine or other 2,5-disubstituted pyrazines can also be prepared for conventional formulation.

Among the metal salt complexes of the 2,5-substituted pyrazines as described herein, those formed with zinc salts, such as zinc chloride, zinc bromide, zinc phosphate, zinc sulfate, zinc nitrate, zinc acetate, zinc carbonate and the like, are preferred. In preparing these complexes, conventional procedures are employed to give complexes having either 1:1 or 2:1 ratios of pyrazine to metal salt. The 221 complex is preferred because it provides a higher proportion of active material per unit weight. Bringing together the desired metal salt and substituted pyrazine in a common solvent, with stirring, is sufiicient to produce the desired complex in high yield. A molar excess of substituted pyrazine will give a 2:1 ratio of pyrazine to metal salt, less than a molar excess giving the 1:1 complex.

The term unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specification for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for therapeutic use as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms, as heretofore described, are tablets, capsules, pills, powder packets, wafers, cachets, granules, solutions or suspensions for oral or sterile injectable use, suppositories, and segregated multiples of any of the foregoing, and other forms alluded to herein.

The following examples illustrate the best mode contemplated by the inventor for carrying out the invention but are not to be construed as limiting the scope thereof.

Example 1.Soft gelatin capsules A batch of 1,000 soft gelatin capsules, each containing mg. of 2,5-dimethylpyrazine in mineral oil, is prepared from the following materials:

\Grams 2,5-dimethylpyrazine 100 Mineral oil, USP 100 A uniform dispersion of the active ingredient in the mineral oil is prepared and the dispersion filled into soft gelatin capsules by conventional means.

One capsule is given twice a day in the treatment of hyperlipidemia.

Example 2.--Compressed tablets A lot of 10,000 compressed tablets, each containing 100 mg. of Z-methyl-S-carboxypyrazine, is prepared from the following ingredients:

The Z-methyl-S-carboxypyrazine and terra alba are mixed well, granulated with 7.5% solution of methylcellulose in water, passed through a No. 8 screen and dried at F. The dried granules are passed through a No. 12 screen, mixed thoroughly with the tale and stearate and compressed into tablets.

Example 3.Injectable preparation An injectable preparation is made from the following ingredients to contain 500 mg. of 2-methyl-5-ethoxycarbonylpyrazine per ml.

The previously sterilized active ingredient is homogenized with the already mixed and sterilized vehicle.

Six thousand units of insulin can be added to the above formulation to give a combination product administrable in 0.5 ml. amounts or less daily.

The novel 2-methyl-5-ethoxycarbonylpyrazine can be prepared by adding ml. of thionyl chloride to 13.8 gm. (0.1 mole) of Z-methyl-5-carboxypyrazine (Beil. [4], 25, 126) in 200 ml. of dry benzene. The mixture is heated under reflux for two hours and the benzene and excess thionyl chloride removed by distillation under vacuum. The residue is added to 25 ml. of anhydrous ethanol and the mixture heated under reflux for one hour. The excess ethanol is removed by distillation under vacuum and the residue purified by recrystallization to give substantially pure Z-methyl-5-ethoxycarbonylpyrazine.

Other lower alkyl esters are prepared by substituting the appropriate alkanol for the ethanol in the above reaction. Acid addition salts are prepared by contacting the free base with the appropriate acid in the usual manner.

Example 4 An aqueous oral suspension containing, in each 5 ml., 200 mg. of 2-methyl-S-carbamoylpyrazine (Chem. Abstr. 42zP5055i [1948]) is prepared from the following materials:

2-methyl-5-carbamoylpyrazine gm 400.0 Methylparaben, USP gm 7.5 Propylparaben, USP gm 2.5 Saccharin sodium gm 12.5 Cyclamate sodium gm 2.5 Glycerin ml 3000.0 Tragacanth powder ..-gm 100.0 Orange oil flavor gm 10.0 F. D. and C. orange dye gm 7.5 Deionized water ml q.s-.. 10,0000

Example 5.--Hard gelatin capsules A lot of 10,000 two-piece hard gelatin capsules for oral use, each containing 100 mg. of N,N-dimethyl-2- methyl-S-carbamoylpyrazine, is prepared from the following materials:

fGrams N,N-dimethyl-2-methyl-S-carbamoylpyrazine 1000.0 Potassium chloride 1000.0 Mineral oil, USP 129.6 Magnesium stearate, powder 162.0 Talc, USP 162.0 Corn starch 1616.0

of dimethylamine is added dropwise with cooling in an ice bath. When addition is complete the mixture is stirred overnight at room temperature. The mixture is then filtered and the filtrate concentrated to dryness. The

crude product is purified by recrystallization from ethanolwater to give substantially pure N,N-dimethyl-2-methyl- -carbamoylpyrazine.

N-methyl-Z-methyl-S-carbamoylpyrazine is prepared by substituting a solution of excess methylamine in benzene in place of the dimethylamine above.

Other N,N-dialkyland N-alkyl-Z-methyl-S-carbamoylpyrazines are prepared as above by substituting the appropriate dialkylor monoalkyl amine for the dimethylamine.

The salts for incorporation in formulations such as above are illustratively represented as follows:

2,5-dimethylpyrazine hydrochloride.To a cold solution of 54 ml. (0.5 mole) of 2,5-dimethylpyrazine in 5 00 ml. of anhydrous ether was added 200 ml. of a 2.8N ethereal-hydrochloride solution. The hydrochloride solution was added over a 20-minute period keeping the reaction temperature at 10-15 C. The mixture was stirred for /2 hr., then filtered and washed with ether to give 66.4 gm. (92%) of product which melted at l58l59 C. After three recrystallizations from isopropanol there was obtained 36 gm. (50%) of product which melts at l65.5 C. (turns greenish-black on melting).

Analysis.Calcd. for C H N Cl: C, 49.83; H, 6.27; N, 19.38; Cl, 24.52. Found: C, 49.43; H, 6.24; N, 19.06; Cl, 24.48. Infrared and NMR spectra support the structure.

2,5-dimethylpyrazine nitrate.T0 a cold solution of 15 ml. (0.15 mole) of 2,5-dimethylpyrazine in 15 ml. of isopropanol was slowly added 10 ml. (0.158 mole) of concentrated nitric acid. The mixture was stirred in an ice bath for 15 minutes and 16 ml. of anhydrous ether was added. The reaction mixture was filtered and washed with cold isopropanol and ether to give 13 gm. (50%) of the purple product which melted at 83-85 C. This material was recrystallized from isopropanol to give 9 gm. (35%) of the product in long purple needles which melt at 84-85 C.

Analysis.-Calcd. for C H N O C. 42.10; H, 5.30; N, 24.55. Found: C, 41.73; H, 5.37; N, 24.40. Infrared spectrum supports the structure.

2,5-dimethylpyrazine p-toluenesulfonate.To a solution of 10 gm. (0.058 mole) of p-toluenesulfonic acid in 20 ml. of isopropanol was added 5 ml. (0.05 mole) of 2,5-dimethylpyrazine. The solution was stirred for a few minutes and then seeded at which point it solidified. The reaction mixture was filtered and washed with isopropanol and ether. The product was recrystallized two times from isopropanol to give 7 gm. (50%) of product which melts at 144.5146 C. The product was colorless and is not volatile.

Analysis.--Calcd. for C H N O S: C. 55.69; H, 5.75; N, 10.00; S, 11.44. Found: C, 55.95; H, 5.75; N, 9.91; S, 11.10. Infrared spectrum supports the structure.

This novel salt is distinguished by unusual suitability for pharmaceutical formulation, particularly in terms of such properties as non-volatility and stability.

Example 6 wherein R and R are hereinbefore defined, gives compositions useful as indicated.

Other complementary ingredients and combinations as illustratively disclosed are added in amounts not exceeding 7 8 those r 1orma1ly emplcyed for each dosage unit when such OTHER REFERENCES- 3 s= 4 Dalmer et' a1. (Merck) Chem. Abst. vol. 30, column at alme 6894 (1936) qdi.A51.

1. 2,5-dimethy1pyrazine p-toluenesulfonate.

5 HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

References Cited UNITED STATES PATENTS 3,067,199 12/ 1962 Langdon 260-250 USCLXR.

FOREIGN PATENTS 10 260242; 424--240, 243, 250

597,889 2/19'48 Great Britain. 

